1. Field of the Invention
The invention relates to novel compounds of formula (I), defined herein, a process for their use in production of 1,1-dioxopenicillanoyloxymethyl 6-(2-amino-2-phenylacetamido)penicillanate antibiotics of formula (II), certain halomethyl (and related) esters of 6-halo (or 6,6-dihalo)penicillanic acid and the corresponding sulfoxides and sulfones useful in preparing compounds of formula (I).
2. Description of the Prior Art
U.S. Pat. No. 4,234,579, issued Nov. 18, 1980, discloses penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo, their use as antibacterial agents and for enhancing the effectiveness of beta-lactam antibiotics against many beta-lactamase producing bacteria.
U.S. Pat. No. 4,244,951, issued Jan. 13, 1981, discloses novel antibacterial agents of formula (VIII) in which penicillinic acid 1,1-dioxide is linked to known penicillin antibiotics via a methylenedioxo group, i.e., ##STR2## where R.sup.b is the acyl group of a natural or semisynthetic penicillin. Especially preferred values for R.sup.b include 2-amino-2-phenylacetyl and 2-amino-2-(p-hydroxyphenyl)acetyl. The compounds (VIII) are prepared, for example, by reacting a carboxylate salt of the penicillin such as the sodium, potassium or tertiary amine salt with a halomethyl ester (or related ester) of penicillanic acid 1,1-dioxide. The intermediate halomethyl esters are prepared by esterification of penicillanic acid 1,1-dioxide.
Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976) disclose: (a) the oxidation of 6,6-dibromopenicillanic acid with m-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; (b) oxidation of methyl 6,6-dibromopenicillanate with m-chlorperbenzoic acid to give a methyl 6,6-dibromopenicillanate 1,1-dioxide; (c) oxidation of methyl 6-alpha-chloropenicillanate with m-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; and (d) oxidation of methyl 6-bromopenicillanate with m-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides.
Clayton, Journal of the Chemical Society (London) (C), 2123 (1969), discloses: (a) the preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; (b) oxidation of 6,6-dibromopenicillanic acid with sodium periodate, to give a mixture of the corresponding sulfoxides; (c) hydrogenolysis of methyl 6,6-dibromopenicillanate to give methyl 6-alpha-bromopenicillanate; (d) hydrogenolysis of 6,6-dibromopenicillanic acid, and its methyl ester, to give penicillanic acid and its methyl ester, respectively; and (e) hydrogenolysis of a mixture of methyl 6,6-diodopenicillanate and methyl 6-alpha-iodopenicillanate to give pure methyl 6-alpha-iodopenicillanate.
Belgian Pat. No. 882,028, granted Sept. 9, 1980, discloses a process for preparing penicillanic acid 1,1-dioxide and its readily hydrolyzable in vivo esters by oxidation of 6-halopenicillanate or a 6,6-dihalopenicillanate to the corresponding 1,1-dioxide, then dehalogenation to provide the desired penicillanate 1,1-dioxide.
U.S. Pat. No. 3,293,242 discloses 6-(2-azido-2-phenylacetamido)penicillanic acid and salts thereof.
Japan Kokai 78-37,691; Chem. Abstr., 89, 109466v (1978) discloses 6-[2-azido-2-(p-hydroxyphenyl)acetamido]penicillanic acid and its reduction with hydrogen and palladium-on-carbon to give 6-[2-amino-2-(p-hydroxyphenyl)acetamido]penicillanic acid.